Since other studies have found reduced binding of these dopamine receptors in both people who are obese and those who have substance use problems, Drs. Kaye and Frank hypothesized that they would find just the opposite in women with anorexia.

By University of Pittsburgh Medical Center,Just why those with anorexia nervosa are driven to be excessively thin and seem unaware of the seriousness of their condition could be due to over-activity of a chemical system found in a region deep inside the brain, a University of Pittsburgh study suggests. Reporting in the journal Biological Psychiatry, researchers found an over-activity of dopamine receptors in the brain's basal ganglia, an area known to play a role in how people learn from experience and make choices.

Results of the study, led by Walter Kaye, M.D., of the University of Pittsburgh School of Medicine, and Guido Frank, M.D., now of the University of California at San Diego, contribute to the understanding of what may cause anorexia. The disorder affects about 1 percent of American women, some of whom die from complications of the disease. The research may point to a molecular target for development of more effective treatments than those currently available.

The study is the first to use positron emission tomography (PET) imaging to assess the activity of brain dopamine receptors, a neurotransmitter system that is best known for its role in controlling movement. These receptors also are associated with weight and feeding behaviors and responses to reinforcement and reward. Researchers used a harmless molecule designed to bind to the dopamine D2 and D3 receptors that lie on the membrane surface of neurons. Ten women who had recovered from anorexia nervosa for more than a year were studied, as were 12 normal female subjects. Because malnourishment affects brain chemistry, the researchers did not include acutely ill women in their study.

Since other studies have found reduced binding of these dopamine receptors in both people who are obese and those who have substance use problems, Drs. Kaye and Frank hypothesized that they would find just the opposite in women with anorexia.

Indeed, there was increased receptor binding in the basal ganglia's antero-ventral striatum in the women with a history of anorexia nervosa irrespective of their age, body mass index or time since recovery, but not in any of the healthy women. The antero-ventral striatum is an area known to modulate reward and reinforcement and is therefore important in learning from experience.

The researchers also found increased dopamine D2/D3 receptor activity in another part of the basal ganglia called the dorsal caudate, which is related to responses to and avoidance of harm. Such activity may help explain why women with anorexia exhibit exaggerated worry and concern about what might happen in the future.

"When they are ill, people with anorexia nervosa don't seek or respond to the kinds of comforts and pleasures most of us enjoy, including food. They also resist and ignore feedback that signifies their precarious state of health. They don't see an emaciated figure in the mirror, they ignore the most obvious warning signs and dismiss comments from loved ones that suggest they are seriously and medically ill. People with anorexia nervosa have extreme self-denial, not only of food, but often of many comforts and pleasures in life. Yet people with anorexia nervosa can be very energetic and productive," said Dr. Kaye, professor of psychiatry.

"Taken together, the alterations in the dopamine system may help explain the tell-tale symptoms of anorexia," added Dr. Kaye.

Alteration in dopamine function may affect the value of perceived rewards, or perhaps make it difficult to associate good feelings with things most people find rewarding, Dr. Kaye explained. Consequently, people with anorexia nervosa may appear to be obsessive about certain stimuli that may be uniquely rewarding to them, but may not be able to respond well to stimuli related to food or pleasure.

"This finding may help us better understand brain dopamine function across a whole spectrum of disorders, with respect to its contribution to the avoidance of food and other stimuli in anorexia nervosa on one end, and the desire for stimuli, such as in food and drug use on the other," added Dr. Frank, a fellow in child psychiatry.

More research is needed to address the many questions that remain, including what causes the dopamine receptors to be overactive in the first place. Genetic studies could yield some answers. Indeed, a study supported by the Price Foundation, which was recently published in the online edition of Neuropsychopharmacology, found alterations in genes for the D2 receptor in some individuals with anorexia nervosa. Dr. Kaye is a co-author of that paper and principal investigator of the Price Foundation studies, including a new multi-center study that is now recruiting families with two or more members who have or had anorexia nervosa to help identify the genes that contribute to the eating disorder.

In addition to Drs. Kaye and Frank, other authors include Carolyn C. Meltzer, M.D., Julie C. Price, Ph.D., Chester A. Mathis, Ph.D., Jessica Hoge and Scott Ziolko, all of the University of Pittsburgh School of Medicine department of radiology; Ursula F. Bailer, M.D., Shannon E. Henry and Angela Wagner, M.D., from the University of Pittsburgh School of Medicine department of medicine; Lisa Weissfeld, Ph.D., from the University of Pittsburgh Graduate School of Public Health department of biostatistics; Wayne Drevits, M.D., from the National Institute of Mental Health; and Nicole Barbarich-Marsteller from the State University of New York at Stony Brook. The research was supported by the National Institute of Mental Health (NIMH) and the Price Foundation. More information about the multi-center study funded by the NIMH can be found at www.angenetics.org.